Quinuclidine esters process and intermediate for their preparation and pharmaceutical compositions containing them

ABSTRACT

Compounds of formula (I) wherein X is either (a) a phenyl group optionally substituted by 1 or 2 substituents each independently selected from halo, CF 3 , C 1  -C 4  alkyl, C 1  -C 4  alkoxy and hydroxy or (b) a thienyl group; and Y is of formula (Ya) or (Yb) where A and B are 0, 1 or 2, D and E are 0 or 1, F is 0-3 and D+E+F=1-3, Z is 0, 1 or 2, R 1  and R 2  are H or alkyl or form a ring, and R 3  is C 1  -C 4  alkyl, C 3  -C 6  cycloalkyl or optionally substituted phenyl or benzyl, are antimuscarinic bronchodilators useful for treating chronic obstructive airways disease or asthma.

This application is the national phase of PCT/EP92/02067 filed on Sep.3, 1992.

BACKGROUND OF THE INVENTION

This invention relates to 3-quinuclidinyl esters specifically to certain3-quinuclidinyl 3-hydroxymethyl 2-phenyl or thienyl alkanoates which arelung-selective antimuscarinic bronchodilators. Thus these compounds areparticularly useful in the treatment of chronic obstructive airwaysdisease (COAD) and asthma.

COAD is a term encompassing conditions which exhibit, to differingextents, several major progressively developing clinicopathologicalfeatures, namely inflammatory swelling of airway walls, hypertrophy ofsubmucosal glands, and hyperplasia of epithelial secretory cells leadingto hypersecretion of viscous muscous which cannot be clearedeffectively, progressive increase in irreversible bronchospasm anddecrease in lung function, with respiratory impairment, increasingmorbidity and, finally, death.

Thus COAD, and also asthma, are diseases of reduced lung function inwhich antimuscarinic bronchodilators are known to improve airwaypatency. However, existing agents are non-selective for smooth musclemuscarinic sites in lung and this reduces their effectiveness asbronchodilators and leads to unwanted side effects. Sub-types ofmuscarinic receptor are now known to exist in the airways (see P. J.Barnes, P. Minette and J. Maclagan, TIPS, 1988, 9, 412.); M1 receptorsare present on sympathetic nerves and parasympathetic ganglia; M2receptors on pulmonary cholinergic nerves (pre-junctional inhibitoryreceptors) and M3 receptors are located on smooth muscle(post-junctional receptors). The compounds of the present inventiongenerally have bronchospasmolytic effects at doses which do notsignificantly affect other tissues such as brain, heart,gastro-intestinal tract, eye and salivary gland. Furthermore theygenerally show selectivity for the lung post-junctional M₃ receptors asopposed to the pulmonary. pre-junctional M₂ receptors and cardiac M₂receptors. Therapeutic action at some other smooth muscle sites may beenvisaged. For example, the compounds are also likely to be useful intreating urinary incontinence.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula (I): ##STR2## or apharmaceutically acceptable salt thereof, wherein X is either (a) aphenyl group optionally substituted by 1 or 2 substituents eachindependently selected from halo, CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy andhydroxy or (b) a thienyl group;

and Y is either (a) a group of formula (Ya) ##STR3## where A and B areindependently 0, 1 or 2, or (b) a group of formula (Yb) ##STR4## where Dand E are independently 0 or 1, F is 0, 1, 2 or 3 and D+E+F=1, 2 or 3,

Z is 0, 1 or 2,

R₁ and R₂ are independently H or C₁ -C₄ alkyl, or R₁ and R₂ are joinedtogether to form, with the carbon atom to which they are attached, a 3-to 6- membered carbocyclic ring, and

R³ is a C₁ -C₄ alkyl group, a cycloalkyl group or a phenyl or benzylgroup optionally substituted by up to 3 substituents each independentlyselected from halo, CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy and hydroxy.

"Halo" means F, Cl, Br or I. C₃ and C₄ alkyl and alkoxy groups may bestraight or branched chain.

X is preferably an unsubstituted phenyl group. When Y is of formula (Ya)R₁ and R₂ are preferably H or, when A=1 and B=0, R₁ and R₂ arepreferably independently H, methyl or ethyl. R₃ is preferably a methylgroup.

The compounds of formula (I) have two asymmetric centres, at thepositions identified as 2 and 3' in formula (I) above. When R₁ and R₂are different the compounds have a third asymmetric centre at the carbonatom to which R₁, and R₂ are attached, and when Z=1 there is a fourthasymmetric centre at the sulphur atom. All diastereoisomers whetherseparated or not are within the scope of the invention. The preferredcompounds are however the 3R-quinuclidinyl esters. Also the preferredstereochemistry at the 2- position is S when the hydrocarbon moiety of Yadjacent the 2-position has at least two carbon atoms. Thus thepreferred compounds are (2S,3'R) 3-quinuclidinyl esters and can berepresented as follows: ##STR5## When Z=1 the preferred stereochemistryat the sulphur atom is R, the moiety containing the sulphur atom thenbeing represented as follows: ##STR6##

A particularly preferred individual compound of the invention is(R)-3-quinuclidinyl(2S,Rs)-2-hydroxymethyl-4-(methylsulphinyl)-2-phenylbutanoate.

The compounds of formula (I) in which Z is 0 can be prepared by thereaction of an ester of the formula (II) with a strong base such aslithium or potassium diisopropylamide, potassium t-butoxide or sodiumhydride to form a carbanion, followed by reaction of the carbanion withformaldehyde. The formaldehyde is generally provided either asformaldehyde gas, or as paraformaldehyde (which breaks down toformaldehyde in solution). ##STR7##

The preferred techniques are as follows.

In one technique, the ester (II) is reacted for a few hours with lithiumdiisopropylamide in tetrahydrofuran at about -78° C. The reactionmixture is then slowly allowed to warm to room temperature during whichtime formaldehyde gas, generated e.g. by heating paraformaldehyde, isintermittently passed into the solution.

In another technique, sodium hydride, the ester (II) andparaformaldehyde are reacted together in dimethylformamide at about roomtemperature.

Compounds (I) having R stereochemistry at position 3' are preferred, andthese are best obtained by starting with an ester (II) having Rstereochemistry at position 3' in formula (II). Likewise the 3Squinuclidinyl esters can be prepared from esters (II) having Sstereochemistry at the 3'-position.

It is usually most convenient to start with the 2 RS forms of the esters(II) even if the 2R or 2S, rather than 2RS, end products are required.This will result in a mixture of diastereomers of the compounds (I),and, if desired, these can be separated into the 2R and 2S forms byconventional techniques such as chromatography. As stated above, ingeneral, the (2S,3'R) forms of the compounds (I) are preferred when thehydrocarbon moiety of Y has at least two carbon atoms.

The compounds of formula (I) in which Z=1 or 2 may be prepared byoxidation of the corresponding compounds in which Z=0. A suitableoxidising agent is pertrifluoroacetic acid. One method is to add asolution of pertrifluoro acetic acid in trifluoroacetic acid to thecompound dissolved in trifluoroacetic acid at a low temperature, such as-10° C., allow the mixture to warm to ambient temperature and evaporatethe solution when reaction is complete. The desired compound may beobtained by solvent extraction of the residue. If the sulphonyl compound(Z=2) is desired an excess of pertrifluoroacetic acid may be used, ifthe sulphinyl compound (Z=1) is to be made the stoichiometric amount ofpertrifluoroacetic acid should be used and the temperature kept low. Amixture of Rs and Ss stereoisomers of the sulphinyl compounds isgenerally obtained and these may be separated by conventional methodssuch as chromatography.

The starting materials (II) also form part of this invention. They areobtainable by conventional techniques such as the following: ##STR8##

The reaction is typically carried out by heating the reactants in anorganic solvent such as toluene at reflux. The compound (III) is mostconveniently used in the RS form, and preferably as the methyl ester.

Alternatively, an acid of formula (IIIA): ##STR9## may be converted tothe corresponding acyl halide, for example by reaction with oxalylchloride in chloroform, and the halide allowed to react with the3-quinuclidinol to form the compound of formula (II).

In general the materials of formula (III) may be made by reaction of anacid of formula X--CH₂ --CO₂ H with a compound of formula Y-Hal, whereHal is chlorine, bromine or iodine, in the presence of a strong basesuch as lithium di-isopropylamide in an anhydrous solvent such astetrahydrofuran, followed by acidification, to produce a compound offormula X--CH(CO₂ H)--Y. This compound may then be converted to thecorresponding ester of formula (III) by conventional methods, forexample by reaction with methanol or ethanol in the presence ofsulphuric acid.

In another method of making compounds of formula (III), a thiol offormula R₃ --SH reacts with an acid of formula (IV): ##STR10## where Y'is the hydrocarbon moiety of group Y in formula (I) and Hal is Cl, Br orI, generally in the presence of a strong base such as sodium hydride,followed by esterification.

When Y is a --CH₂ --S--R₃ group the compound of formula (II) may also beprepared by reaction of a compound of formula R₃ --S--H with a compoundof formula (V) in the presence of a strong base: ##STR11## The compoundof formula (II) may then be treated with formaldehyde and a base toyield the compound of formula (I).

The selectivity of the compounds as muscarinic receptor antagonists canbe measured as follows.

Male guinea pigs are sacrificed and the ileum, trachea, bladder andright atrium are removed and suspended in Krebs solution under a restingtension of 1 g at 30° C. aerated with 95% O₂ and 5% CO₂. Contractions ofthe ileum, bladder and trachea are recorded using an isotonic (ileum) orisometric transducer (bladder and trachea). The frequency of contractionof the spontaneously beating double atria is derived from isometricallyrecorded contractions.

Dose-response curves to carbachol are determined using a 1-5 minutecontact time for each dose to agonist until the maximum response isachieved. The organ bath is drained and refilled with Krebs solutioncontaining the lowest dose of the test compound. The test compound isallowed to equilibrate with the tissue for 20 minutes and the agonistdose-response curve is repeated until the maximum response is obtained.The organ bath is drained and refilled with Krebs solution containingthe second concentration of test compound and the above procedure isrepeated. Typically three concentrations of the test compound areevaluated on each tissue.

The negative log of the molar concentration (pA₂) of the test compoundwhich causes a doubling of the agonist concentration to produce theoriginal response is determined by Schild analysis (Arunlakshana andSchild (1959), Brit. J. Pharmacol., 14, 48-58). Using the abovepharmacological techniques, tissue selectivity for muscarinic receptorantagonists is determined.

Activity against agonist-induced or nerve-evoked bronchoconstriction orgut or bladder contractility in comparison with changes in heart rate isdetermined in the anaesthetised dog, cat or guinea pig. Oral activity isassessed in the conscious dog determining compound effects on lungfunction, heart rate, pupil diameter and gut motility.

Compound affinity for other cholinergic sites is assessed in the mouseafter either intravenous or intraperitoneal administration. Thus, thedose which causes a doubling of pupil size is determined as well as thedose which inhibits the salivation and tremor responses to intravenousoxotremorine by 50%.

The selectivity of the compounds for pulmonary post-junctional asagainst pre-junctional muscarinic receptors in anaesthetised guinea pigsand cats can be assessed by the following techniques. Acetylcholinereleased by nerve stimulation activates post-junctional M3 muscarinicreceptors to cause contraction of airway smooth muscle and, in addition,activates pre-junctional autoreceptors which inhibit further transmitterrelease. Animal studies indicate that these pulmonary pre-junctionalmuscarinic autoreceptors are of the M2 subtype (Barnes et al, 1989).Non-selective agents like ipratropium bromide will inhibit both sites,resulting, in the case of nerve-mediated responses, in an increase intransmitter release which can overcome the post-junctional receptorblockade. Published literature has shown that ipratropium bromide canactually potentiate vagally-induced bronchoconstriction in anaesthetisedguinea pigs (Fryer and Maclagan, Eur. Jou. Pharmacol., 139, 187-191(1987)). Thus, the effects of the test compounds on pre- andpost-junctional muscarinic sites can be determined in vivo by comparingthe effect on nerve mediated responses with the effect on responses toexogenously adminstered acetylcholine.

For example, the compound of Example 29 has been found to antagoniseboth acetylcholine-induced, and vagally-induced, bronchoconstriction inanaesthetised guinea pigs over the same dose range. This contrasts withipratropium bromide which is significantly less potent againstvagally-induced than against acetylcholine-induced bronchoconstriction.Additionally, at doses below 1 μg/kg of ipratropium bromide,vagally-induced bronchoconstriction is actually potentiated, confirmingits pre-junctional effects.

Similar results were obtained from the compound of Example 29 in theanaesthetised cat. The animals were pretreated with propranolol becausehigh sympathetic tone under chloralose anaesthesia may opposepotentiation of vagus nerve-induced bronchoconstriction. The testresults indicate that, in addition to its high potency, the compound ofExample 29, in contrast to ipratropium bromide, does not interruptnegative feedback control of transmitter release in both guinea-pig andcat. This confirms the demonstrated in vitro selectivity of thiscompound for M3 as opposed to M2 muscarinic receptors.

As a result of this selectivity for post- as opposed to pre-junctionalmuscarinic receptors, the compounds of the invention should be moreeffective bronchodilators in respiratory disease compared to ipratropiumbromide.

The acid addition salts of the compounds of formula (I) can be preparedin a conventional manner by treating a solution or suspension of thefree base of (I) with about one chemical equivalent of apharmaceutically acceptable acid. Conventional concentration andrecrystallization techniques are employed in isolating the salts.Illustrative of suitable acids are acetic, lactic, succinic, maleic,tartaric, citric, ascorbic, benzoic, cinnamic, fumaric, sulphuric,phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonicsuch as methanesulfonic, benzenesulfonic, and related acids.

For treatment of the various conditions described above the compounds offormula (I) may be administered to a subject in need of treatment by avariety of conventional routes of administration, including oraladministration, and in an aerosol or dry powder composition foradministration by inhalation. The compounds have potential forabsorption through the gastro-intestinal tract and thus administrationby slow release formulations is also possible.

In general, a therapeutically-effective oral dose of the activecompounds of formula (I) is likely to range from 0.01 to 1 mg/kg bodyweight of the subject to be treated, preferably 0.1 to 0.5 mg/kg. Inpractice the physician will determine the actual dosage which will bemost suitable for an individual patient and it will vary with age,weight and response of the particular patient. The above dosages areexemplary of the average case but there can, of course, be individualinstances where higher or lower dosages ranges are merited, and such arewithin the scope of this invention.

Although the compounds of formula (I) can be administered alone, theywill generally be administered in admixture with a pharmaceuticalcarrier selected with regard to the intended route of administration andstandard pharmaceutical practice. For example, oral administration maybe in the form of tablets containing such excipients as starch orlactose, in capsules either alone or in admixture with excipients, inaerosol or dry powder inhaler form, or in the form of elixirs orsuspensions containing flavouring or colouring agents.

In a further aspect the invention provides a pharmaceutical compositioncomprising a compound Of the formula (I), or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablediluent or carrier.

The invention also includes a compound of the formula (I) or apharmaceutically acceptable salt thereof, for use as a medicament.

The invention further includes the use of a compound of the formula (I),or of a pharmaceutically acceptable salt thereof, for the manufacture ofa medicament for the treatment of chronic obstructive airways disease orasthma.

Preparation of compounds according to the invention is illustrated bythe following Examples.

EXAMPLE 1 (R)-3-Quinuclidinyl (R andS)-3-hydroxy-2-(methylthiomethyl)-2-phenylpropanoate ##STR12##

Sodium hydride (2 mg, as an 80% dispersion in oil) was added to amixture of (R)-3-quinuclidinyl-2-phenylacrylate (see Preparation 1)(1.03 g) and methane thiol (2 ml, of a 10% wt/vol solution inchloroform) in chloroform (8 ml). After 1 hour the mixture wasevaporated, and the residue in dimethylformamide (2.5 ml) added to aprestirred (5 min) mixture of paraformaldehyde (240 mg) and sodiumhydride (1 mg of an 80% dispersion in oil) in dimethylformamide (10 ml).After 2 hours the mixture was partitioned between ethylacetate andwater. The organic layer was washed with water, dried over magnesiumsulphate and evaporated to leave a residue that was purified bychromatography on silica gel performing a gradient elution usingchloroform plus methanol (0→10%) and ammonia (0→1%) as eluant.Appropriate fractions were combined and evaporated to give the two titlecompounds, of undefined stereochemistry at C2 as white solids.

Diastereoisomer 1 (higher Rf by tlc) (0.27 g, 40% based on singleisomer), m.p. 143°-145° C.

Analysis %: Found: C,64.07; H,7.35; N,4.25; C₁₈ H₂₅ NO₃ S requires:C,64.44; H,7.51; N,4.18.

Diastereoisomer 2 (lower Rf by tlc) (0.17 g, 25% based on singleisomer), m.p. 122°-123° C.

Analysis %: Found: C,64.23; H,7.39; N,4.25; C₁₈ H₂₅ NO₃ S requires:C,64.44; H,7.51; N,4.18.

EXAMPLE 2 (R)-3-Quinuclidinyl (R andS)-2-hydroxymethyl-4-(methylthio)-2-phenylbutanoate ##STR13##

Sodium hydride (3×20 mg portions, as an 80% dispersion in oil) was addedover 1 hour to a mixture of (R)-3-quinuclidinyl(RS)-4-(methylthio)-2-phenylbutanoate (see Preparation 2) (22 g) andparaformaldehyde (6.2 g) in dimethylformamide (90 ml) at roomtemperature. After two hours saturated aqueous ammonium chloride (100ml) was added at 0° C. and the mixture evaporated. The residue waspartitioned between ethylacetate and water, the organic layer dried overmagnesium sulphate, and evaporated to give a residue that was purifiedby chromatography on silica gel performing a gradient elution usingchloroform plus methanol (0→10%) and ammonia (0→1%) as eluant.Appropriate fractions were combined and evaporated to give the two titlecompounds, with the stereochemistry at C₂ as indicated, as white solids.

Diastereoisomer 1 (R) stereochemistry (4 g, 33% based on single isomer)m.p. 109°-110° C.

Analysis %: Found: C,65.60; H,7.92; N,4.01; C₁₉ H₂₇ NO₃ S requires:C,65.29; H,7.79; N,4.01.

Diastereoisomer 2 (S) stereochemistry (4.4 g, 37% based on singleisomer) m.p. 134°-135° C.

Analysis %: Found: C,65.09; H,7.84; N,3.94; C₁₉ H₂₇ NO₃ S requires:C,65.29; H,7.79; N,4.01.

EXAMPLES 3 TO 10

The following Examples of Table 1 of the general formula: ##STR14## wereobtained by similar methods to that described in Example 2 byhydroxymethylation of the appropriately substituted (R)-3-quinuclidinylesters. Individual experimental variations are indicated in the table."Diastereoisomers 1 and 2" merely refer to their relative positioning ontlC.

                                      TABLE 1                                     __________________________________________________________________________    Ex.               Experimental                                                No.                                                                              R              Variations  Analytical Data                                 __________________________________________________________________________        ##STR15##                                                                                    ##STR16##                                                                                 ##STR17##                                      4                                                                                 ##STR18##                                                                                    ##STR19##                                                                                 ##STR20##                                      5                                                                                 ##STR21##                                                                                    ##STR22##                                                                                 ##STR23##                                      6                                                                                 ##STR24##                                                                                    ##STR25##                                                                                 ##STR26##                                      7                                                                                 ##STR27##                                                                                    ##STR28##                                                                                 ##STR29##                                      8                                                                                 ##STR30##                                                                                    ##STR31##                                                                                 ##STR32##                                      9                                                                                 ##STR33##                                                                                    ##STR34##                                                                                 ##STR35##                                      __________________________________________________________________________

EXAMPLE 10 (R)-3-Quinuclidinyl (R andS)-2-hydroxymethyl-4-methyl-4-(methylthio)-2-phenylpentanoate ##STR36##

Lithium diisopropylamide (5.7 ml of a 1.5M solution in cyclohexane) wasadded to a solution of (R)-3quinuclidinyl(RS)-4-methyl-4-(methylthio)-2phenylpentanoate (see Preparation 4) (2.7g) in tetrahydrofuran (50 ml) at -78° C. After 2 hours the reaction wasallowed to slowly reach room temperature during which time formaldehydegas [generated by heating paraformaldehyde (1.5 g) in a stream ofnitrogen] was intermittently added. Saturated ammonium chloride was thenadded and the product extracted with ethylacetate. The organic layer wasdried over magnesium sulphate and evaporated under reduced pressure togive a residue that was purified by chromatography on silica gel usingethylacetate: ether: diethylamine: methanol (50:50:5:5) as eluant.Appropriate fractions were combined and evaporated to give the two titlecompounds, of undefined stereochemistry at C₂ as white solids.

Diastereoisomer 1 (higher Rf by tlc) (0.35 g, 24% based on singleisomer) m.p. 179°-180° C.

Analysis %: Found: C,66.56; H,8.37; N,3.49; C₂₁ H₃₁ NO₃ S requires:C,66.80; H,8.28; N,3.71.

Diastereoisomer 2 (lower Rf by tlc) (0.31 g, 21% based on single isomer)m.p. 135°-137° C.

Analysis %: Found: C,66.48; H,8.32; N,3.45; C₂₁ H₃₁ NO₃ S requires:C,66.80; H,8.28; N,3.71.

EXAMPLE 11 (R)-3-Quinuclidinyl (R orS)-3-hydroxy-2-(methylsulphonylmethyl)-2-phenylpropanoate ##STR37##

Pertrifluoroacetic acid (0.36 ml of a 3M solution in trifluoroaceticacid) was added to (R)-3-quinuclidinyl (R orS)-3-hydroxy-2-(methylthiomethyl)-2-phenylpropanoate, diastereoisomer 2(see Example 1), hydrochloride salt (0.2 g) in trifluoroacetic acid (2ml) at 5° C. The mixture was stirred for 1/4 of an hour, warmed to 30°C., stirred for 1 hour and evaporated to give a residue that waspartitioned between aqueous 10% potassium carbonate and ethylacetate.The organic layer was dried over sodium sulphate, evaporated, and theresidue purified by chromatography on silica gel performing a gradientelution using chloroform plus methanol (0→10%) and aqueous ammonia(0→1%) as eluant. Appropriate fractions were combined and evaporated togive the title compound, a single diastereoisomer of undefinedstereochemistry at C₂, as a white solid, (90 mg 43%), m.p. 136°-137° C.

Analysis %: Found: C,58.84; H,6.86; N,3.81; C₁₈ H₂₅ NO₅ S requires:C,58.66; H,6.62; N,3.65.

EXAMPLE 12(R)-3-Quinuclidinyl(S)-2-hydroxymethyl-4-(methylsulphonyl)-2-phenylbutanoat##STR38##

Pertrifluoroacetic acid (0.36 ml of a 3M solution in trifluoroaceticacid) was added to (R)-3-quinuclidinyl(S)-2-hydroxymethyl-4-(methylthio)-2-phenylbutanoate (see Example 2)(0.189 g) in trifluoroacetic acid (2 ml) at -10° C. The mixture waswarmed to room temperature, stirred for 1 hour and evaporated. Theresidue was partitioned between aqueous 10% potassium carbonate andchloroform, the organic layer dried over sodium sulphate and evaporated.The residue was purified by chromatography on silica gel performing agradient elution using chloroform plus methanol (0→10%) and aqueousammonia (0→1%) as eluant. Appropriate fractions were combined andevaporated to give the title compound as a white solid, (0.155 g, 74%),m.p. 154°-155° C.

Analysis %: Found: C,59.65; H,7.19; N,3.58; C₁₉ H₂₇ NO₅ S requires:C,59.82; H,7.14; N,3.67.

EXAMPLES 13 TO 20

The following Examples of Table 2 of the general formula: ##STR39## wereobtained by similar methods to that described in Example 12 by oxidationof the appropriate sulphide. The starting sulphides, of undefinedstereochemistry at C₂, were always the diastereoisomer of lower Rf ontlc described in the appropriate Example. Individual experimentalvariations are indicated in the table.

                                      TABLE 2                                     __________________________________________________________________________    Ex.              Experimental                                                 No.                                                                              XSY           Variations   Analytical Data                                 __________________________________________________________________________    13                                                                                ##STR40##                                                                                   ##STR41##                                                                                  ##STR42##                                      14                                                                                ##STR43##                                                                                   ##STR44##                                                                                  ##STR45##                                      15                                                                                ##STR46##                                                                                   ##STR47##                                                                                  ##STR48##                                      16                                                                                ##STR49##                                                                                   ##STR50##                                                                                  ##STR51##                                      17                                                                                ##STR52##                                                                                   ##STR53##                                                                                  ##STR54##                                      18                                                                                ##STR55##                                                                                   ##STR56##                                                                                  ##STR57##                                      19                                                                                ##STR58##                                                                                   ##STR59##                                                                                  ##STR60##                                      20                                                                                ##STR61##                                                                                   ##STR62##                                                                                  ##STR63##                                      __________________________________________________________________________

EXAMPLE 21 (R)-3-Quinuclidinyl (2 R or S, R_(s)S_(s))-3-hydroxy-2-(methylsulphinylmethyl)-2-phenylpropanoate ##STR64##

Pertrifluoroacetic acid (0.33 ml of a 3M solution in trifluoroaceticacid) was added to (R)-3-quinuclidinyl (R orS)-3-hydroxy-2-(methylthiomethyl)-2-phenylpropanoate, diastereoisomer 2,(see Example 1) (0.335 g) in trifluoroacetic acid (3 ml) at -5° C. Themixture was stirred for 1/2 hour, warmed to room temperature, stirred afurther 1 hour and evaporated. The residue was partitioned betweenaqueous 10% potassium carbonate and ethylacetate, the organic layerdried over sodium sulphate and evaporated. The residue was purified bychromatography on silica, performing a gradient elution using chloroformplus methanol (0→10%) and aqueous ammonia (0→1%) as eluant. Appropriatefractions were combined and evaporated to give the title compound asingle diastereoisomer of undefined stereochemistry at C₂ as a whitesolid, (0.14 g, 40%), m.p. 126°-127° C.

Analysis %: Found: C,61.49; H,7.24; N,3.79; C₁₈ H₂₅ NO₄ S requires:C,61.51; H,7.17; N,3.99.

EXAMPLES 22 TO 28

The following Examples of Table 3 of the general formula: ##STR65## wereobtained by similar methods to that described in Example 21 by oxidationof the appropriate sulphide. The starting sulphides, of undefinedstereochemistry at C₂ were always the second diastereoisomer of lower Rfon tlc described in the appropriate Example. No attempts were made toseparate sulphoxide isomers. Individual experimental variations areindicated in the table.

                                      TABLE 3                                     __________________________________________________________________________    Ex.              Experimental                                                 No.                                                                              XSY           Variations  Analytical Data                                  __________________________________________________________________________    22                                                                                ##STR66##                                                                                   ##STR67##                                                                                 ##STR68##                                       23                                                                                ##STR69##                                                                                   ##STR70##                                                                                 ##STR71##                                       24                                                                                ##STR72##                                                                                   ##STR73##                                                                                 ##STR74##                                       25                                                                                ##STR75##                                                                                   ##STR76##                                                                                 ##STR77##                                       26                                                                                ##STR78##                                                                                   ##STR79##                                                                                 ##STR80##                                       27                                                                                ##STR81##                                                                                   ##STR82##                                                                                 ##STR83##                                       28                                                                                ##STR84##                                                                                   ##STR85##                                                                                 ##STR86##                                       __________________________________________________________________________

EXAMPLE 29 (R)-3-Quinuclidinyl (2S, R_(s) &S_(s))-2-hydroxymethyl-4-methylsulphinyl)-2-phenylbutanoate ##STR87##

Pertrifluoroacetic acid (4 ml of a 3M solution in trifluoroacetic acid)was added to(R)-3-quinuclidinyl-(S)-2-hydroxymethyl-4-(methylthio)-2-phenylbutanoate(see Example 2) (4.19 g) in trifluoroacetic acid (18 ml) at between -3°and 0° C. The mixture was warmed to room temperature, stirred for 1 hourand evaporated. The residue was partitioned between aqueous 10%potassium carbonate and chloroform, the organic layer dried over sodiumsulphate and evaporated. The residue was chromatographed on silica,performing a gradient elution using chloroform plus methanol (0→15%) andaqueous ammonia (0→1.5%) as eluant. Appropriate fractions were combinedand evaporated to give the title compounds (4 g 91%) as a 50:50 mixtureof R_(s) and S_(s) diastereoisomers.

This mixture (2×250 mg) was purified by high performance liquidchromatography on Kromasil C-8 silica using water containingtrifluoroacetic acid (1%) and acetonitrile (11%) as eluant. Appropriatefractions were combined and evaporated to give the two title compoundswith the stereochemistry at sulphur as indicated, as white solids.

Diastereoisomer 1 (first eluted isomer) (S_(s)) stereochemistry (70 mg,28%, based on single isomer) m.p. 153°-155° C.

Analysis %: Found: C,62.47; H,7.55; N,3.84; C₁₉ H₂₇ NO₄ S requires:C,62.43; H,7.45; N,3.83.

Diastereoisomer 2 (second eluted isomer) (R_(s)) stereochemistry (70 mg,28%, based on single isomer) m.p. 84°-85° C.

Analysis %: Found: C,62.19; H,7.45; N,3.81; C₁₉ H₂₇ NO₄ S requires:C,62.43; H,7.45; N,3.83.

The following Preparations relate to intermediates for making compoundsof the invention.

PREPARATION 1 (R)-3-Quinuclidinyl-2-phenylacrylate ##STR88##

Oxalyl chloride (44.2 ml) was added to a solution of 2-phenylacrylicacid (50 g) (prepared as described in J. Chem. Soc., 2557, 123, 1923)and dimethylformamide (0.5 ml) in chloroform (500 ml). The mixture wasstirred for 1/2 hour, dimethylformamide (0.5 ml) was added and themixture was stirred for a further 1/2 hour, then evaporated to give aresidue to which chloroform (2×100 ml) was added and evaporated. Theresidue was finally dissolved in chloroform (500 ml) and to thissolution at 10°-15° C. was added (R)-3-quinuclidinol (prepared asdescribed in Acta. Pharm. Suec., 281, 16, 1979) dissolved in chloroform(500 ml). The mixture was stirred for 1/2 hour, allowed to slowly reachroom temperature, evaporated and the residue partitioned between 25%aqueous potassium carbonate and ether. The organic layer was dried overmagnesium sulphate, evaporated and the residue recrystallised fromhexane to give the title compound, as a white solid, (66 g, 76%) m.p.83°-85° C.

Analysis %: Found: C,74.39; H,7.47; N,5.45; C₁₆ H₁₉ NO₂ requires:C,74.67; H,7.44; N,5.44.

PREPARATION 2 (R)-3-Quinuclidinyl (RS)-4-(methylthio)-2-phenylbutanoate##STR89##

Sodium hydride (0.64 g, as an 80% dispersion in oil) was added to amixture of methyl-(RS)-4-(methylthio)-2-phenylbutanoate (see Preparation11) (19.1 g) and (R)-3-quinuclidinol (prepared as described in Acta.Pharm. Suec., 281, 16, 1979) (12.7 g) in toluene (440 ml). The mixturewas refluxed with continuous removal of distillate and when necessaryreplacement with fresh toluene for 1.5 hours. The cooled mixture wasextracted with 2M hydrochloric acid, the aqueous layer washed withethylacetate, basified with potassium carbonate and extracted withchloroform. The organic layer was dried over sodium sulphate, evaporatedand the residue partitioned between ethylacetate and aqueous 10%potassium carbonate. The organic layer was dried over sodium sulphateand evaporated to leave the title compound (22.4 g, 82%) as a yellowoil.

¹ H-N.M.R. (300 MHz, CDCl₃) δ=1.1-1.7(m, 6H), 1.8-2.2(m,6H),2.2-2.8(m,5H), 3.1(m,1H), 3.7(t,1H), 4.7(m,1H), 7.2 (m,5H) ppm.

PREPARATIONS 3 TO 6

The following preparations of Table 4 of the general formula: ##STR90##were obtained by similar methods to that described in Preparation 2, byan ester exchange reaction between the appropriately substitutedphenylacetic acid methyl ester and R-3-quinuclidinol. Individualexperimental variations are indicated in the table, diastereoisomerswere not separated.

                                      TABLE 4                                     __________________________________________________________________________    Prep.               Experimental                                              No. Ester           Variations  Analytical Data                               __________________________________________________________________________         ##STR91##                                                                                     ##STR92##                                                                                 ##STR93##                                    4                                                                                  ##STR94##                                                                                                 ##STR95##                                    5                                                                                  ##STR96##                                                                                                 ##STR97##                                    6                                                                                  ##STR98##                                                                                     ##STR99##                                                                                 ##STR100##                                   __________________________________________________________________________

PREPARATION 7 (R)-3-Quinuclidinyl (RS)-4-(ethylthio)-2-phenylbutanoate##STR101##

Oxalyl chloride (0.9 ml) in chloroform (2 ml) was added to a solution of(RS)-4-(ethylthio)-2-phenylbutanoic acid (see Preparation 16) (2.0 g)and dimethylformamide (10 μl) in chloroform (20 ml) at room temperature.After 2 hours the mixture was evaporated, and the residue in chloroform(20 ml) treated at 0° C. with (R)-3-quinuclidinol (1.27 g) in chloroform(10 ml). The mixture was allowed to reach room temperature, stirred for3 hours and then washed with 10% aqueous potassium carbonate. Theorganic layer was washed with water, dried over sodium sulphate andevaporated to give the title compound (2.3 g, 78%) as a yellow oil.

Analysis %: Found: C,68.24; H,8.06; N,4.48; C₁₉ H₂₇ NO₂ S requires:C,68.63; H,8.19; N,4.21.

PREPARATIONS 8 TO 10

The following preparations of Table 5 of the general formula: ##STR102##were obtained by similar methods to that described in Preparation 7, byesterification of an appropriately substituted phenylacetic acid with(R)-3-quinuclidinol. Individual experimental variations are indicated inthe table, diastereoisomers were separated only in Preparation 8.

                                      TABLE 5                                     __________________________________________________________________________    Prep.                    Experimental                                         No. Acid                 Variations  Analytical Data                          __________________________________________________________________________         ##STR103##                                                                                         ##STR104##                                                                                ##STR105##                              9                                                                                  ##STR106##                                                                                                     ##STR107##                              10                                                                                 ##STR108##                                                                                                     ##STR109##                              __________________________________________________________________________

PREPARATION 11 Methyl (RS)-4-(methylthio)-2-phenylbutanoate ##STR110##

Lithium diisopropylamide (450 ml of a 1.5M solution in cyclohexane) wasadded to a stirred solution of phenylacetic acid (40.8 g) intetrahydrofuran (300 ml) at between 0° and 5° C. The mixture was warmedto room temperature, stirred for 1.5 hours, treated with2-chloroethylmethylsulphide (30 ml) in tetrahydrofuran 30 ml, refluxedfor 2 hours, cooled and evaporated. To the residue in methanol (200 ml)was added concentrated sulphuric acid (50 ml) in methanol (250 ml), themixture refluxed for 1.5 hours, and evaporated. The residue waspartitioned between water and chloroform, the organic layer washed withaqueous 10% potassium carbonate, dried over sodium sulphate andevaporated to give a light brown oil (55 g). A portion of this (33 g)was distilled to give the title compound (24.5 g, 61%) as a clear liquidb.p. 128°-135° C. at 5 mm Hg.

¹ H-N.M.R. (300 MHz, CDCl₃) δ=2.0(m,4H), 2.2-2.5(m,3H), 3.6(s,3H),3.7(m,1H), 7.1-7.4(m,5H) ppm.

PREPARATIONS 12-15

The following preparations of table 6 of the general formula: ##STR111##were obtained by similar methods to that described in preparation 7 byalkylation of the di-anion derived from phenylacetic acid with theappropriately substituted chloroethylsulphide (R-Cl). Individualvariations are indicated in the table.

                                      TABLE 6                                     __________________________________________________________________________    Prep.             Experimental                                                No. RCl           Variations       Analytical Data                            __________________________________________________________________________    12                                                                                 ##STR112##                                                                                  ##STR113##                                                                                     ##STR114##                                13                                                                                 ##STR115##                                                                                  ##STR116##                                                                                     ##STR117##                                14                                                                                 ##STR118##                                                                                  ##STR119##                                                                                     ##STR120##                                15                                                                                 ##STR121##                                                                                  ##STR122##                                                                                     ##STR123##                                __________________________________________________________________________

PREPARATION 16 (RS)-4-(Ethylthio)-2-phenylbutanoic Acid ##STR124##

(RS)-4-Bromo-2-phenylbutanoic acid (prepared as described in Farmaco(pavia) Ed. Sci. 355 21(5) 1966) (2.43 g) in dimethylformamide (5 ml)was added to a stirred suspension of sodium hydride (0.33 g, as an 80%dispersion in oil) and ethanethiol sodium salt (1.26 g) indimethylformamide (15 ml) at 0° C. The mixture was warmed to roomtemperature, stirred for 2 hours and evaporated. The residue waspartitioned between water and ethylacetate, the aqueous layer acidifiedwith concentrated hydrochloric acid and extracted with ethylacetate. Theorganic layer was dried over sodium sulphate and evaporated to give thetitle compound (2 g, 89%) as an oil.

Analysis %: Found: C,64.07; H,7.08; C₁₂ H₁₆ O₂ S requires: C,64.25;H,7.19.

PREPARATION 17 (RS)-4-(isopropylthio)-2-phenylbutanoic Acid ##STR125##

The title compound, as an oil, was prepared by a similar method to thatdescribed in Preparation 16 using isopropylthiol sodium salt (generatedin-situ from sodium hydride and isopropylthiol) in place of ethanethiolsodium salt.

¹ H-N.M.R. (300 MHz, CDCl₃) δ=1.25(m,6H), 2.1(m,1H), 2.3-2.5(m,3H),2.7-3.0(m,2H), 3.8(t,1H), 7.2-7.5(m,5H) ppm.

PREPARATION 18 (RS)-5-(Methylthio)-2-phenylpentanoic Acid ##STR126##

The title compound, as an oil was prepared by a similar method to thatdescribed in Preparation 16 using (RS)-5-bromo-2-phenylpentanoic acid(prepared as described in Arkio., For., Kemi., 431, 1957) in place of(RS)-4-bromo-2-phenylpentanoic acid.

¹ -N.M.R. (300 MHz, CDCl₃) δ=1.5(m,2H), 1.8(m, 1H), 2.0(s,3H), 2.1(m,1H), 2.4(t,2H), 3.5(t,1H), 7.25(s,5H) ppm.

PREPARATION 19 (RS)-6-Methylthio-2-phenylhexanoic Acid ##STR127##

The title compound, as a yellow oil, was prepared by a similar method tothat described in Preparation 16 using (RS)-6-bromo-2-phenylhexanoicacid in place of (RS) -bromo-2-phenylbutanoic acid (prepared asdescribed in British Patent No. 1,309,375). ₁ H-N.M.R. (300 MHz, CDCl₃)δ=1.3(m,2H), 1.6(m,2H), 1.8(m, 1H), 2.1(m,4H), 2.45(t,2H), 3.55(m, 1H),7.1-7.5(m,5H) ppm.

We claim:
 1. A compound of formula (I): ##STR128## or a pharmaceuticallyacceptable salt thereof, wherein X is either(a) a phenyl groupoptionally substituted by 1 or 2 substituents each independentlyselected from halo, CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy and hydroxy, or (b)A thienyl group; and Y is either (a) a group of formula (Ya) ##STR129##where A and B are independently 0, 1 or 2 or (b) a group of formula (Yb)##STR130## where D and E are independently 0 or 1, F is 0, 1, 2 or 3 andD+E+F=1, 2 or 3; Z is 0, 1 or 2, R₁ and R₂ are independently H or C₁ -C₄alkyl, or R₁ and R₂ are joined together to form, with the carbon atom towhich they are attached, a 3- or 6-membered saturated or unsaturatedcarbocyclic ring, and R₃ is a C₁ -C₄ alkyl group, a C₃ -C₆ cycloalkylgroup or a phenyl or benzyl group optionally substituted by up to 3substituents each independently selected from halo, CF₃, C₁ -C₄ alkyl,C₁ -C₄ alkoxy and hydroxy.
 2. A compound according to claim 1, in whichX is an unsubstituted phenyl group.
 3. A compound according to claim 2,in which Y is of formula (Ya) and R₁ and R₂ are both H.
 4. A compoundaccording to claim 2 in which Y is of formula (Ya), A is 1, B is 0 andR₁ and R₂ are independently H, methyl or ethyl.
 5. A compound accordingto claim 4, in which R₃ is methyl.
 6. A compound according to claim 5,of R-stereochemistry at the 3' position and S-stereochemistry at the 2position having the formula (Ia): ##STR131##
 7. A compound according toclaim 6, in which Z is 1 and having R-stereochemistry at the sulphuratom of Y, the moiety containing the sulphur atom being of formula:##STR132##
 8. (R)-3-Quinuclidinyl(2S,R_(s))-2-hydroxymethyl-4-(methylsulphinyl)-2-phenylbutanoate.
 9. Apharmaceutical composition comprising a compound of formula (I) or (Ia)claim 1, or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable diluent or carrier.
 10. A compound offormula (II): ##STR133## wherein X and Y are as claimed in claim
 1. 11.A method of treatment of chronic obstructive airways disease or asthma,which comprises administering to a patient an effective amount of acompound according to claim 1.